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Antigen receptor diversification and chromosome translocations

Nature Immunology volume 8, pages 801–808 (2007)Cite this article

Abstract

Double-stranded DNA breaks (DSBs) can result in chromosomal abnormalities, including deletions, translocations and aneuploidy, which can promote neoplastic transformation. DSBs arise accidentally during DNA replication and can be induced by environmental factors such as ultraviolet light or ionizing radiation, and they are generated during antigen receptor–diversification reactions in lymphocytes. Cellular pathways that maintain genomic integrity use sophisticated mechanisms that recognize and repair all DSBs regardless of their origin. Such pathways, along with DNA-damage checkpoints, ensure that either the damage is properly repaired or cells with damaged DNA are eliminated. Here we review how impaired DNA-repair or DNA-damage checkpoints can lead to genetic instability and predispose lymphocytes undergoing diversification of antigen receptor genes to malignant transformation.

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Figure 1: DSBs mediated by RAG proteins can be channeled toward translocation.
Figure 2: Molecular requirements for efficient CSR and protection from translocations.

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References

  1. Meffre, E., Casellas, R. & Nussenzweig, M.C. Antibody regulation of B cell development. Nat. Immunol. 1, 379–385 (2000).

    CAS  PubMed  Google Scholar 

  2. Fugmann, S.D., Lee, A.I., Shockett, P.E., Villey, I.J. & Schatz, D.G. The RAG proteins and V(D)J recombination: complexes, ends, and transposition. Annu. Rev. Immunol. 18, 495–527 (2000).

    CAS  PubMed  Google Scholar 

  3. Brandt, V.L. & Roth, D.B.V. (D)J recombination: how to tame a transposase. Immunol. Rev. 200, 249–260 (2004).

    CAS  PubMed  Google Scholar 

  4. Alt, F.W. et al. Ordered rearrangement of immunoglobulin heavy chain variable region segments. EMBO J. 3, 1209–1219 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003).

    CAS  PubMed  Google Scholar 

  6. Gay, D., Saunders, T., Camper, S. & Weigert, M. Receptor editing: an approach by autoreactive B cells to escape tolerance. J. Exp. Med. 177, 999–1008 (1993).

    CAS  PubMed  Google Scholar 

  7. Tiegs, S.L., Russell, D.M. & Nemazee, D. Receptor editing in self-reactive bone marrow B cells. J. Exp. Med. 177, 1009–1020 (1993).

    CAS  PubMed  Google Scholar 

  8. Casellas, R. et al. Contribution of receptor editing to the antibody repertoire. Science 291, 1541–1544 (2001).

    CAS  PubMed  Google Scholar 

  9. Schwickert, T.A. et al. In vivo imaging of germinal centres reveals a dynamic open structure. Nature 446, 83–87 (2007).

    CAS  PubMed  Google Scholar 

  10. Stavnezer, J. Antibody class switching. Adv. Immunol. 61, 79–146 (1996).

    CAS  PubMed  Google Scholar 

  11. Kinoshita, K., Harigai, M., Fagarasan, S., Muramatsu, M. & Honjo, T. A hallmark of active class switch recombination: transcripts directed by I promoters on looped-out circular DNAs. Proc. Natl. Acad. Sci. USA 98, 12620–12623 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Zarrin, A.A. et al. Antibody class switching mediated by yeast endonuclease-generated DNA breaks. Science 315, 377–381 (2007).

    CAS  PubMed  Google Scholar 

  13. Muramatsu, M. et al. Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells. J. Biol. Chem. 274, 18470–18476 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Muramatsu, M. et al. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102, 553–563 (2000).

    CAS  PubMed  Google Scholar 

  15. Revy, P. et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell 102, 565–575 (2000).

    CAS  PubMed  Google Scholar 

  16. Petersen-Mahrt, S.K., Harris, R.S. & Neuberger, M.S. AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature 418, 99–103 (2002).

    CAS  PubMed  Google Scholar 

  17. Di Noia, J. & Neuberger, M.S. Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase. Nature 419, 43–48 (2002).

    CAS  PubMed  Google Scholar 

  18. Rada, C., Di Noia, J.M. & Neuberger, M.S. Mismatch recognition and uracil excision provide complementary paths to both Ig switching and the A/T-focused phase of somatic mutation. Mol. Cell 16, 163–171 (2004).

    CAS  PubMed  Google Scholar 

  19. Ramiro, A.R., Stavropoulos, P., Jankovic, M. & Nussenzweig, M.C. Transcription enhances AID-mediated cytidine deamination by exposing single-stranded DNA on the nontemplate strand. Nat. Immunol. 4, 452–456 (2003).

    CAS  PubMed  Google Scholar 

  20. Dickerson, S.K., Market, E., Besmer, E. & Papavasiliou, F.N. AID mediates hypermutation by deaminating single stranded DNA. J. Exp. Med. 197, 1291–1296 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Chaudhuri, J. et al. Transcription-targeted DNA deamination by the AID antibody diversification enzyme. Nature 422, 726–730 (2003).

    CAS  PubMed  Google Scholar 

  22. Bransteitter, R., Pham, P., Scharff, M.D. & Goodman, M.F. Activation-induced cytidine deaminase deaminates deoxycytidine on single-stranded DNA but requires the action of RNase. Proc. Natl. Acad. Sci. USA 100, 4102–4107 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Barreto, V.M. et al. AID from bony fish catalyzes class switch recombination. J. Exp. Med. 202, 733–738 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Ichikawa, H.T. et al. Structural phylogenetic analysis of activation-induced deaminase function. J. Immunol. 177, 355–361 (2006).

    CAS  PubMed  Google Scholar 

  25. Wakae, K. et al. Evolution of class switch recombination function in fish activation-induced cytidine deaminase, AID. Int. Immunol. 18, 41–47 (2006).

    CAS  PubMed  Google Scholar 

  26. Petersen, S. et al. AID is required to initiate Nbs1/γ-H2AX focus formation and mutations at sites of class switching. Nature 414, 660–665 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Honjo, T., Nagaoka, H., Shinkura, R. & Muramatsu, M. AID to overcome the limitations of genomic information. Nat. Immunol. 6, 655–661 (2005).

    CAS  PubMed  Google Scholar 

  28. Schrader, C.E., Linehan, E.K., Mochegova, S.N., Woodland, R.T. & Stavnezer, J. Inducible DNA breaks in Ig S regions are dependent on AID and UNG. J. Exp. Med. 202, 561–568 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Larson, E.D., Cummings, W.J., Bednarski, D.W. & Maizels, N. MRE11/RAD50 cleaves DNA in the AID/UNG-dependent pathway of immunoglobulin gene diversification. Mol. Cell 20, 367–375 (2005).

    CAS  PubMed  Google Scholar 

  30. Arlt, M.F., Durkin, S.G., Ragland, R.L. & Glover, T.W. Common fragile sites as targets for chromosome rearrangements. DNA Repair (Amst.) 5, 1126–1135 (2006).

    CAS  Google Scholar 

  31. Adams, J.M. et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318, 533–538 (1985).

    CAS  PubMed  Google Scholar 

  32. Strasser, A. et al. Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. Proc. Natl. Acad. Sci. USA 88, 8661–8665 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Madisen, L. & Groudine, M. Identification of a locus control region in the immunoglobulin heavy-chain locus that deregulates c-myc expression in plasmacytoma and Burkitt's lymphoma cells. Genes Dev. 8, 2212–2226 (1994).

    CAS  PubMed  Google Scholar 

  34. Kuppers, R. & Dalla-Favera, R. Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene 20, 5580–5594 (2001).

    CAS  PubMed  Google Scholar 

  35. Shiloh, Y. ATM and related protein kinases: safeguarding genome integrity. Nat. Rev. Cancer 3, 155–168 (2003).

    CAS  PubMed  Google Scholar 

  36. Borghesani, P.R. et al. Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice. Proc. Natl. Acad. Sci. USA 97, 3336–3341 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Elson, A. et al. Pleiotropic defects in ataxia-telangiectasia protein-deficient mice. Proc. Natl. Acad. Sci. USA 93, 13084–13089 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Xu, Y. et al. Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev. 10, 2411–2422 (1996).

    CAS  PubMed  Google Scholar 

  39. Barlow, C. et al. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86, 159–171 (1996).

    CAS  PubMed  Google Scholar 

  40. Liyanage, M. et al. Abnormal rearrangement within the α/δ T-cell receptor locus in lymphomas from Atm-deficient mice. Blood 96, 1940–1946 (2000).

    CAS  PubMed  Google Scholar 

  41. Callén, E. et al. ATM prevents persistence and propagation of chromosome breaks in lymphocytes. Cell advance online publication, 28 June 2007 (doi:10.1016/j.cell.2007.06.016).

    Google Scholar 

  42. Liao, M.J. & Van Dyke, T. Critical role for Atm in suppressing V(D)J recombination-driven thymic lymphoma. Genes Dev. 13, 1246–1250 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Petiniot, L.K. et al. RAG-mediated V(D)J recombination is not essential for tumorigenesis in Atm-deficient mice. Mol. Cell. Biol. 22, 3174–3177 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Difilippantonio, M.J. et al. DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation. Nature 404, 510–514 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Difilippantonio, M.J. et al. Evidence for replicative repair of DNA double-strand breaks leading to oncogenic translocation and gene amplification. J. Exp. Med. 196, 469–480 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Gao, Y. et al. Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development. Nature 404, 897–900 (2000).

    CAS  PubMed  Google Scholar 

  47. Zhu, C. et al. Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations. Cell 109, 811–821 (2002).

    CAS  PubMed  Google Scholar 

  48. Gladdy, R.A. et al. The RAG-1/2 endonuclease causes genomic instability and controls CNS complications of lymphoblastic leukemia in p53/Prkdc-deficient mice. Cancer Cell 3, 37–50 (2003).

    CAS  PubMed  Google Scholar 

  49. Raghavan, S.C., Kirsch, I.R. & Lieber, M.R. Analysis of the V(D)J recombination efficiency at lymphoid chromosomal translocation breakpoints. J. Biol. Chem. 276, 29126–29133 (2001).

    CAS  PubMed  Google Scholar 

  50. Marculescu, R., Le, T., Simon, P., Jaeger, U. & Nadel, B.V. (D)J-mediated translocations in lymphoid neoplasms: a functional assessment of genomic instability by cryptic sites. J. Exp. Med. 195, 85–98 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Raghavan, S.C., Swanson, P.C., Wu, X., Hsieh, C.L. & Lieber, M.R. A non-B-DNA structure at the Bcl-2 major breakpoint region is cleaved by the RAG complex. Nature 428, 88–93 (2004).

    CAS  PubMed  Google Scholar 

  52. Lee, G.S., Neiditch, M.B., Salus, S.S. & Roth, D.B. RAG proteins shepherd double-strand breaks to a specific pathway, suppressing error-prone repair, but RAG nicking initiates homologous recombination. Cell 117, 171–184 (2004).

    CAS  PubMed  Google Scholar 

  53. Dorsett, Y. et al. A role for AID in chromosome translocations between c-myc and the IgH variable region. J. Exp. Med. (in the press).

  54. Jankovic, M., Casellas, R., Yannoutsos, N., Wardemann, H. & Nussenzweig, M.C. RAGs and regulation of autoantibodies. Annu. Rev. Immunol. 22, 485–501 (2004).

    CAS  PubMed  Google Scholar 

  55. Potter, M. Neoplastic development in plasma cells. Immunol. Rev. 194, 177–195 (2003).

    CAS  PubMed  Google Scholar 

  56. Suematsu, S. et al. Generation of plasmacytomas with the chromosomal translocation t(12;15) in interleukin 6 transgenic mice. Proc. Natl. Acad. Sci. USA 89, 232–235 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Potter, M. & Wiener, F. Plasmacytomagenesis in mice: model of neoplastic development dependent upon chromosomal translocations. Carcinogenesis 13, 1681–1697 (1992).

    CAS  PubMed  Google Scholar 

  58. Unniraman, S., Zhou, S. & Schatz, D.G. Identification of an AID-independent pathway for chromosomal translocations between the Igh switch region and Myc. Nat. Immunol. 5, 1117–1123 (2004).

    CAS  PubMed  Google Scholar 

  59. Ramiro, A.R. et al. AID is required for c-myc/IgH chromosome translocations in vivo. Cell 118, 431–438 (2004).

    CAS  PubMed  Google Scholar 

  60. Ramiro, A.R. et al. Role of genomic instability and p53 in AID-induced c-myc-Igh translocations. Nature 440, 105–109 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Gordon, M.S., Kanegai, C.M., Doerr, J.R. & Wall, R. Somatic hypermutation of the B cell receptor genes B29 (Igβ, CD79b) and mb1 (Igα, CD79a). Proc. Natl. Acad. Sci. USA 100, 4126–4131 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Shen, H.M., Peters, A., Baron, B., Zhu, X. & Storb, U. Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes. Science 280, 1750–1752 (1998).

    CAS  PubMed  Google Scholar 

  63. Wyman, C. & Kanaar, R. DNA double-strand break repair: all's well that ends well. Annu. Rev. Genet. 40, 363–383 (2006).

    CAS  PubMed  Google Scholar 

  64. Goossens, T., Klein, U. & Kuppers, R. Frequent occurrence of deletions and duplications during somatic hypermutation: implications for oncogene translocations and heavy chain disease. Proc. Natl. Acad. Sci. USA 95, 2463–2468 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Wilson, P.C. et al. Somatic hypermutation introduces insertions and deletions into immunoglobulin V genes. J. Exp. Med. 187, 59–70 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Sale, J.E. & Neuberger, M.S. TdT-accessible breaks are scattered over the immunoglobulin V domain in a constitutively hypermutating B cell line. Immunity 9, 859–869 (1998).

    CAS  PubMed  Google Scholar 

  67. Papavasiliou, F.N. & Schatz, D.G. Cell-cycle-regulated DNA double-stranded breaks in somatic hypermutation of immunoglobulin genes. Nature 408, 216–221 (2000).

    CAS  PubMed  Google Scholar 

  68. Kong, Q. & Maizels, N. DNA breaks in hypermutating immunoglobulin genes: evidence for a break-and-repair pathway of somatic hypermutation. Genetics 158, 369–378 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Bross, L., Muramatsu, M., Kinoshita, K., Honjo, T. & Jacobs, H. DNA double-strand breaks: prior to but not sufficient in targeting hypermutation. J. Exp. Med. 195, 1187–1192 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Ronai, D. et al. Detection of chromatin-associated single-stranded DNA in regions targeted for somatic hypermutation. J. Exp. Med. 204, 181–190 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Kotani, A. et al. A target selection of somatic hypermutations is regulated similarly between T and B cells upon activation-induced cytidine deaminase expression. Proc. Natl. Acad. Sci. USA 102, 4506–4511 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Okazaki, I.M. et al. Constitutive expression of AID leads to tumorigenesis. J. Exp. Med. 197, 1173–1181 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Kotani, A. et al. Activation-induced cytidine deaminase (AID) promotes B cell lymphomagenesis in Emu-cmyc transgenic mice. Proc. Natl. Acad. Sci. USA 104, 1616–1620 (2007).

    PubMed  PubMed Central  Google Scholar 

  74. Endo, Y. et al. Expression of activation-induced cytidine deaminase in human hepatocytes via NF-κB signaling. Oncogene advance online publication; 2 April 2007 (doi:10.1038/sj.onc.1210344). (2007).

    Google Scholar 

  75. Matsumoto, Y. et al. Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. Nat. Med. 13, 470–476 (2007).

    CAS  PubMed  Google Scholar 

  76. Abraham, R.T. PI 3-kinase related kinases: 'big' players in stress-induced signaling pathways. DNA Repair (Amst.) 3, 883–887 (2004).

    CAS  Google Scholar 

  77. Sancar, A., Lindsey-Boltz, L.A., Unsal-Kacmaz, K. & Linn, S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu. Rev. Biochem. 73, 39–85 (2004).

    CAS  PubMed  Google Scholar 

  78. Falck, J., Coates, J. & Jackson, S.P. Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 434, 605–611 (2005).

    CAS  PubMed  Google Scholar 

  79. Zhou, J., Lim, C.U., Li, J.J., Cai, L. & Zhang, Y. The role of NBS1 in the modulation of PIKK family proteins ATM and ATR in the cellular response to DNA damage. Cancer Lett. 243, 9–15 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Pan-Hammarstrom, Q. et al. Disparate roles of ATR and ATM in immunoglobulin class switch recombination and somatic hypermutation. J. Exp. Med. 203, 99–110 (2006).

    PubMed  PubMed Central  Google Scholar 

  81. Stracker, T.H., Theunissen, J.W., Morales, M. & Petrini, J.H. The Mre11 complex and the metabolism of chromosome breaks: the importance of communicating and holding things together. DNA Repair (Amst.) 3, 845–854 (2004).

    CAS  Google Scholar 

  82. Fernandez-Capetillo, O., Lee, A., Nussenzweig, M. & Nussenzweig, A. H2AX: the histone guardian of the genome. DNA Repair (Amst.) 3, 959–967 (2004).

    CAS  Google Scholar 

  83. Chen, H.T. et al. Response to RAG-mediated VDJ cleavage by NBS1 and γ-H2AX. Science 290, 1962–1965 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Celeste, A. et al. Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks. Nat. Cell Biol. 5, 675–679 (2003).

    CAS  PubMed  Google Scholar 

  85. Difilippantonio, S. et al. Role of Nbs1 in the activation of the Atm kinase revealed in humanized mouse models. Nat. Cell Biol. 7, 675–685 (2005).

    CAS  PubMed  Google Scholar 

  86. Hsieh, C.L., Arlett, C.F. & Lieber, M.R.V. (D)J recombination in ataxia telangiectasia, Bloom's syndrome, and a DNA ligase I-associated immunodeficiency disorder. J. Biol. Chem. 268, 20105–20109 (1993).

    CAS  PubMed  Google Scholar 

  87. Perkins, E.J. et al. Sensing of intermediates in V(D)J recombination by ATM. Genes Dev. 16, 159–164 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Bredemeyer, A.L. et al. ATM stabilizes DNA double-strand-break complexes during V(D)J recombination. Nature 442, 466–470 (2006).

    CAS  PubMed  Google Scholar 

  89. McKinnon, P.J. ATM and ataxia telangiectasia. EMBO Rep. 5, 772–776 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Lumsden, J.M. et al. Immunoglobulin class switch recombination is impaired in Atm-deficient mice. J. Exp. Med. 200, 1111–1121 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Reina-San-Martin, B., Chen, H.T., Nussenzweig, A. & Nussenzweig, M.C. ATM is required for efficient recombination between immunoglobulin switch regions. J. Exp. Med. 200, 1103–1110 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Franco, S. et al. H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Mol. Cell 21, 201–214 (2006).

    CAS  PubMed  Google Scholar 

  93. Lee, J.H. & Paull, T.T. ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science 308, 551–554 (2005).

    CAS  PubMed  Google Scholar 

  94. Difilippantonio, M. J. et al. Distinct domains in Nbs1 regulate irradiation-induced checkpoints and apoptosis. J. Exp. Med. 204, 1003–1011 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Varon, R. et al. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 93, 467–476 (1998).

    CAS  PubMed  Google Scholar 

  96. Carney, J.P. et al. The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 93, 477–486 (1998).

    CAS  PubMed  Google Scholar 

  97. Zhu, J., Petersen, S., Tessarollo, L. & Nussenzweig, A. Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice. Curr. Biol. 11, 105–109 (2001).

    CAS  PubMed  Google Scholar 

  98. Kang, J., Bronson, R.T. & Xu, Y. Targeted disruption of NBS1 reveals its roles in mouse development and DNA repair. EMBO J. 21, 1447–1455 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Williams, B.R. et al. A murine model of Nijmegen breakage syndrome. Curr. Biol. 12, 648–653 (2002).

    CAS  PubMed  Google Scholar 

  100. Yeo, T.C. et al. V(D)J rearrangement in Nijmegen breakage syndrome. Mol. Immunol. 37, 1131–1139 (2000).

    CAS  PubMed  Google Scholar 

  101. Harfst, E. et al. Normal V(D)J recombination in cells from patients with Nijmegen breakage syndrome. Mol. Immunol. 37, 915–929 (2000).

    CAS  PubMed  Google Scholar 

  102. Gregorek, H., Chrzanowska, K.H., Michalkiewicz, J., Syczewska, M. & Madalinski, K. Heterogeneity of humoral immune abnormalities in children with Nijmegen breakage syndrome: an 8-year follow-up study in a single centre. Clin. Exp. Immunol. 130, 319–324 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Reina-San-Martin, B., Nussenzweig, M.C., Nussenzweig, A. & Difilippantonio, S. Genomic instability, endoreduplication, and diminished Ig class-switch recombination in B cells lacking Nbs1. Proc. Natl. Acad. Sci. USA 102, 1590–1595 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Kracker, S. et al. Nibrin functions in Ig class-switch recombination. Proc. Natl. Acad. Sci. USA 102, 1584–1589 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Celeste, A. et al. Genomic instability in mice lacking histone H2AX. Science 296, 922–927 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Bassing, C.H. et al. Increased ionizing radiation sensitivity and genomic instability in the absence of histone H2AX. Proc. Natl. Acad. Sci. USA 99, 8173–8178 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Celeste, A. et al. H2AX haploinsufficiency modifies genomic stability and tumor susceptibility. Cell 114, 371–383 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Bassing, C.H. et al. Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. Cell 114, 359–370 (2003).

    CAS  PubMed  Google Scholar 

  109. Reina-San-Martin, B. et al. H2AX is required for recombination between immunoglobulin switch regions but not for intra-switch region recombination or somatic hypermutation. J. Exp. Med. 197, 1767–1778 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Ramiro, A.R., Nussenzweig, M.C. & Nussenzweig, A. Switching on chromosomal translocations. Cancer Res. 66, 7837–7839 (2006).

    CAS  PubMed  Google Scholar 

  111. Mochan, T.A., Venere, M., DiTullio, R.A., Jr & Halazonetis, T.D. 53BP1, an activator of ATM in response to DNA damage. DNA Repair (Amst.) 3, 945–952 (2004).

    CAS  Google Scholar 

  112. Huyen, Y. et al. Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks. Nature 432, 406–411 (2004).

    CAS  PubMed  Google Scholar 

  113. Botuyan, M.V. et al. Structural basis for the methylation state-specific recognition of histone H4–K20 by 53BP1 and Crb2 in DNA repair. Cell 127, 1361–1373 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Ward, I.M., Minn, K., Jorda, K.G. & Chen, J. Accumulation of checkpoint protein 53BP1 at DNA breaks involves its binding to phosphorylated histone H2AX. J. Biol. Chem. 278, 19579–19582 (2003).

    CAS  PubMed  Google Scholar 

  115. Fernandez-Capetillo, O. et al. DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1. Nat. Cell Biol. 4, 993–997 (2002).

    CAS  PubMed  Google Scholar 

  116. Bekker-Jensen, S., Lukas, C., Melander, F., Bartek, J. & Lukas, J. Dynamic assembly and sustained retention of 53BP1 at the sites of DNA damage are controlled by Mdc1/NFBD1. J. Cell Biol. 170, 201–211 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Ward, I.M., Minn, K., van Deursen, J. & Chen, J. p53 Binding protein 53BP1 is required for DNA damage responses and tumor suppression in mice. Mol. Cell. Biol. 23, 2556–2563 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Ward, I.M. et al. 53BP1 is required for class switch recombination. J. Cell Biol. 165, 459–464 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Manis, J.P. et al. 53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination. Nat. Immunol. 5, 481–487 (2004).

    CAS  PubMed  Google Scholar 

  120. Morales, J.C. et al. Role for the BRCA1 C-terminal repeats (BRCT) protein 53BP1 in maintaining genomic stability. J. Biol. Chem. 278, 14971–14977 (2003).

    CAS  PubMed  Google Scholar 

  121. Reina-San-Martin, B., Chen, J., Nussenzweig, A. & Nussenzweig, M.C. Enhanced intra-switch region recombination during immunoglobulin class switch recombination in 53BP1−/− B cells. Eur. J. Immunol. 37, 235–239 (2007).

    CAS  PubMed  Google Scholar 

  122. Bassing, C.H. & Alt, F.W. The cellular response to general and programmed DNA double strand breaks. DNA Repair (Amst.) 3, 781–796 (2004).

    CAS  Google Scholar 

  123. Lieber, M.R., Ma, Y., Pannicke, U. & Schwarz, K. The mechanism of vertebrate nonhomologous DNA end joining and its role in V(D)J recombination. DNA Repair (Amst.) 3, 817–826 (2004).

    CAS  Google Scholar 

  124. Taccioli, G.E. et al. Impairment of V(D)J recombination in double-strand break repair mutants. Science 260, 207–210 (1993).

    CAS  PubMed  Google Scholar 

  125. Carroll, A.M. & Bosma, M.J. T-lymphocyte development in scid mice is arrested shortly after the initiation of T-cell receptor δ gene recombination. Genes Dev. 5, 1357–1366 (1991).

    CAS  PubMed  Google Scholar 

  126. Casellas, R. et al. Ku80 is required for immunoglobulin isotype switching. EMBO J. 17, 2404–2411 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Manis, J.P. et al. Ku70 is required for late B cell development and immunoglobulin heavy chain class switching. J. Exp. Med. 187, 2081–2089 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Burma, S., Chen, B.P. & Chen, D.J. Role of non-homologous end joining (NHEJ) in maintaining genomic integrity. DNA Repair (Amst.) 5, 1042–1048 (2006).

    CAS  Google Scholar 

  129. Mills, K.D., Ferguson, D.O. & Alt, F.W. The role of DNA breaks in genomic instability and tumorigenesis. Immunol. Rev. 194, 77–95 (2003).

    CAS  PubMed  Google Scholar 

  130. Walker, J.R., Corpina, R.A. & Goldberg, J. Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature 412, 607–614 (2001).

    CAS  PubMed  Google Scholar 

  131. Burma, S. & Chen, D.J. Role of DNA-PK in the cellular response to DNA double-strand breaks. DNA Repair (Amst.) 3, 909–918 (2004).

    CAS  Google Scholar 

  132. Chen, B.P. et al. Ataxia telangiectasia mutated (ATM) is essential for DNA-PKcs phosphorylations at the Thr-2609 cluster upon DNA double strand break. J. Biol. Chem. 282, 6582–6587 (2007).

    CAS  PubMed  Google Scholar 

  133. Gladdy, R.A., Nutter, L.M., Kunath, T., Danska, J.S. & Guidos, C.J. p53-Independent apoptosis disrupts early organogenesis in embryos lacking both ataxia-telangiectasia mutated and Prkdc. Mol. Cancer Res. 4, 311–318 (2006).

    CAS  PubMed  Google Scholar 

  134. Sekiguchi, J. et al. Genetic interactions between ATM and the nonhomologous end-joining factors in genomic stability and development. Proc. Natl. Acad. Sci. USA 98, 3243–3248 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Vogel, H., Lim, D.S., Karsenty, G., Finegold, M. & Hasty, P. Deletion of Ku86 causes early onset of senescence in mice. Proc. Natl. Acad. Sci. USA 96, 10770–10775 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Nussenzweig, A. et al. Requirement for Ku80 in growth and immunoglobulin V(D)J recombination. Nature 382, 551–555 (1996).

    CAS  PubMed  Google Scholar 

  137. Gu, Y. et al. Growth retardation and leaky SCID phenotype of Ku70-deficient mice. Immunity 7, 653–665 (1997).

    CAS  PubMed  Google Scholar 

  138. Taccioli, G.E. et al. Targeted disruption of the catalytic subunit of the DNA-PK gene in mice confers severe combined immunodeficiency and radiosensitivity. Immunity 9, 355–366 (1998).

    CAS  PubMed  Google Scholar 

  139. Gao, Y. et al. A targeted DNA-PKcs-null mutation reveals DNA-PK-independent functions for KU in V(D)J recombination. Immunity 9, 367–376 (1998).

    CAS  PubMed  Google Scholar 

  140. Ouyang, H. et al. Ku70 is required for DNA repair but not for T cell antigen receptor gene recombination in vivo. J. Exp. Med. 186, 921–929 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Bassing, C.H., Swat, W. & Alt, F.W. The mechanism and regulation of chromosomal V(D)J recombination. Cell 109 Suppl, S45–S55 (2002).

    CAS  PubMed  Google Scholar 

  142. Grawunder, U. & Harfst, E. How to make ends meet in V(D)J recombination. Curr. Opin. Immunol. 13, 186–194 (2001).

    CAS  PubMed  Google Scholar 

  143. Bosma, G.C. et al. DNA-dependent protein kinase activity is not required for immunoglobulin class switching. J. Exp. Med. 196, 1483–1495 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Cook, A.J. et al. Reduced switching in SCID B cells is associated with altered somatic mutation of recombined S regions. J. Immunol. 171, 6556–6564 (2003).

    CAS  PubMed  Google Scholar 

  145. Manis, J.P., Dudley, D., Kaylor, L. & Alt, F.W. IgH class switch recombination to IgG1 in DNA-PKcs-deficient B cells. Immunity 16, 607–617 (2002).

    CAS  PubMed  Google Scholar 

  146. Moshous, D. et al. Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell 105, 177–186 (2001).

    CAS  PubMed  Google Scholar 

  147. Rooney, S. et al. Leaky Scid phenotype associated with defective V(D)J coding end processing in Artemis-deficient mice. Mol. Cell 10, 1379–1390 (2002).

    CAS  PubMed  Google Scholar 

  148. Ma, Y., Pannicke, U., Schwarz, K. & Lieber, M.R. Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell 108, 781–794 (2002).

    CAS  PubMed  Google Scholar 

  149. Lobrich, M. & Jeggo, P.A. Harmonising the response to DSBs: a new string in the ATM bow. DNA Repair (Amst.) 4, 749–759 (2005).

    Google Scholar 

  150. Ma, Y., Schwarz, K. & Lieber, M.R. The Artemis:DNA-PKcs endonuclease cleaves DNA loops, flaps, and gaps. DNA Repair (Amst.) 4, 845–851 (2005).

    CAS  Google Scholar 

  151. Goodarzi, A.A. et al. DNA-PK autophosphorylation facilitates Artemis endonuclease activity. EMBO J. 25, 3880–3889 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Moshous, D. et al. Partial T and B lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in Artemis. J. Clin. Invest. 111, 381–387 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Rooney, S. et al. Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells. Proc. Natl. Acad. Sci. USA 101, 2410–2415 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Rooney, S., Alt, F.W., Sekiguchi, J. & Manis, J.P. Artemis-independent functions of DNA-dependent protein kinase in Ig heavy chain class switch recombination and development. Proc. Natl. Acad. Sci. USA 102, 2471–2475 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Costantini, S., Woodbine, L., Andreoli, L., Jeggo, P.A. & Vindigni, A. Interaction of the Ku heterodimer with the DNA ligase IV/Xrcc4 complex and its regulation by DNA-PK. DNA Repair (Amst) 6, 712–722 (2007).

    CAS  Google Scholar 

  156. Mari, P.O. et al. Dynamic assembly of end-joining complexes requires interaction between Ku70/80 and XRCC4. Proc. Natl. Acad. Sci. USA 103, 18597–18602 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Gao, Y. et al. A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis. Cell 95, 891–902 (1998).

    CAS  PubMed  Google Scholar 

  158. Frank, K.M. et al. Late embryonic lethality and impaired V(D)J recombination in mice lacking DNA ligase IV. Nature 396, 173–177 (1998).

    CAS  PubMed  Google Scholar 

  159. Barnes, D.E., Stamp, G., Rosewell, I., Denzel, A. & Lindahl, T. Targeted disruption of the gene encoding DNA ligase IV leads to lethality in embryonic mice. Curr. Biol. 8, 1395–1398 (1998).

    CAS  PubMed  Google Scholar 

  160. Lee, Y., Barnes, D.E., Lindahl, T. & McKinnon, P.J. Defective neurogenesis resulting from DNA ligase IV deficiency requires Atm. Genes Dev. 14, 2576–2580 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Karanjawala, Z.E. et al. The embryonic lethality in DNA ligase IV-deficient mice is rescued by deletion of Ku: implications for unifying the heterogeneous phenotypes of NHEJ mutants. DNA Repair (Amst.) 1, 1017–1026 (2002).

    CAS  Google Scholar 

  162. Ahnesorg, P., Smith, P. & Jackson, S.P. XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell 124, 301–313 (2006).

    CAS  PubMed  Google Scholar 

  163. Buck, D. et al. Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 124, 287–299 (2006).

    CAS  PubMed  Google Scholar 

  164. Zha, S., Alt, F.W., Cheng, H.L., Brush, J.W. & Li, G. Defective DNA repair and increased genomic instability in Cernunnos-XLF-deficient murine ES cells. Proc. Natl. Acad. Sci. USA 104, 4518–4523 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Pan-Hammarstrom, Q. et al. Impact of DNA ligase IV on nonhomologous end joining pathways during class switch recombination in human cells. J. Exp. Med. 201, 189–194 (2005).

    PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Laboratory of Molecular Immunology, The Rockefeller University, New York, 10021-6399, New York, USA

    Mila Jankovic & Michel C Nussenzweig

  2. Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, 20892-1360, Maryland, USA

    André Nussenzweig

  3. Howard Hughes Medical Institute, The Rockefeller University, New York, 10021-6399, New York, USA

    Michel C Nussenzweig

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Jankovic, M., Nussenzweig, A. & Nussenzweig, M. Antigen receptor diversification and chromosome translocations. Nat Immunol 8, 801–808 (2007). https://doi.org/10.1038/ni1498

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